Mood and cognitive orders such as depression affect more than 20 million people each year in the United States. Current therapies have limited efficacy and therefore, it is imperative that we continue to search for new targets to treat these disorders. Adult hippocampal neurogenesis has been implicated in disorders. It has been demonstrated that the generation of new neurons in the hippocampus is essential for efficacy of current antidepressants (Santarelli et al., 2003). Recently, our lab identified leptin as a potential antidepressant (Lu et al., 2006). We have demonstrated that leptin treatment has a neurogenic effect in the hippocampus. The purpose of this proposal is to determine the role that leptin receptor activity in the hippocampus plays in the regulation of adult hippocampal neurogenesis. We hypothesize that leptin receptor activity in the hippocampus regulates neurogenic activity by the activation of specific intracellular mechanisms. To address this we devised the following specific aims. Specific Aim 1 will determine the functional role of LepRb activity in the hippocampus in adult hippocampal neurogenesis.We will address this by generating conditional knockout mice lacking LepRb in the hippocampus using the cre-loxp system. We will determine if LepRb in the hippocampus regulates basal neurogenic activity and mediates the pharmacological effect of leptin on neurogenesis. Specific Aim 2 will identify signal transduction pathways underlying leptin's effect on neurogenesis. LepRb has been linked to activation of multiple intracellular signal transduction pathways, including JAK/STAT, MAPK, and PI3K-AKT. This aim will examine specific signal transduction mechanisms involved in leptin's effects on hippocampal cell proliferation and differentiation both in vitro and in vivo. To address this, first we will establish adult hippocampal stem cell culture to determine whether treatment with specific inhibitors of STATS, MAPK, and Akt can block leptin's effects on neurogenesis. Next will determine whether the signal transduction pathways identified in vitro also mediate leptin's effects in vivo. Identifying the mechanisms by which leptin regulates neurogenesis will reveal potential therapeutic targets for the treatment of cognitive and mood disorders.